The use of elevated temperatures, i.e., hyperthermia, to repress tumors has been under continuous investigation for many years. When normal human cells are heated to 41.degree.-43.degree. C., DNA synthesis is reduced and respiration is depressed. At about 45.degree. C., irreversible destruction of structure, and thus function of chromosome associated proteins, occurs. Autodigestion by.the cell's digestive mechanism occurs at lower temperatures in tumor cells than in normal cells.
In addition, hyperthermia induces an inflammatory response which may also lead to tumor destruction. Cancer cells are more likely to undergo these changes at a particular temperature. This may be due to intrinsic differences, between normal cells and cancerous cells. More likely, the difference is associated with the low pH (acidity), low oxygen content and poor nutrition in tumors as a consequence of decreased blood flow. This is confirmed by the fact that recurrence of tumors in animals, after hyperthermia, is found in the tumor margins; probably as a consequence of better blood supply to those areas.
Conventional methods of cancer treatment are surgery, radiation (X-ray) therapy and chemotherapy. In radiation therapy and chemotherapy, there are important interactions with hyperthermia. Acidity, hypoxia (low oxygen tension) and decreased nutrition all lead to increased susceptibility to hyperthermia treatment. In contrast, these conditions lead to resistance to radiation therapy and chemotherapy. Thus, hyperthermia has been suggested as an adjunct treatment to enhance the other two treatments.
The differences are fundamental. Radiotherapy chiefly affects cells in mitosis (cell division), while hyperthermia is most effective during the DNA synthesis phase. Heat impairs recovery from sublethal radiation damage. When heat and radiation are given together, or heat prior to radiation, there is thermal enhancement of radiation damage to both normal tissue and tumors. However, if radiation therapy is given prior to hyperthermia, thermal enhancement of radiation damage for tumors is greater than normal tissue.
Despite the ability to reasonably define radiation fields and the availability of accurate radiation dosimetry, damage to normal structures, which cannot be avoided, result in dose limiting factors in radiation therapy. Thus, the avoidance of significant hyperthermia to adjacent normal structures is critical for hyperthermia to become a useful adjunct to radiation therapy.
Recent clinical studies support the proposition that radiation therapy and hyperthermia can be combined effectively. In addition, both in vivo and in vitro experiments show that the effects of chemotherapy are also enhanced by hyperthermia. This enhancement may be due to increased membrane permeability at higher temperatures (drugs get into cells more easily) and inhibition of repair mechanisms for drug induced cellular damage. Since chemotherapy is given to the entire body, precise localization of hyperthermia is again essential in combination with chemotherapy to avoid significant damage to normal tissues.
A practical hyperthermia applicator must comply with the following criteria:
1. In order to treat tumors in all areas of the body, depth of penetration is essential. The major limitation to many promising hyperthermia techniques is the inability to achieve high temperatures in deep structures.
2. The applicator must have the ability to focus hyperthermia and quantitate absorbed heat in all areas of the tumor. Studies have shown that very high temperatures (approximately 50.degree. C.) are most effective in cases where this temperature can be achieved. Methods that rely on temperature focusing, rather than on the ability of normal tissues to dissipate heat, allow these temperatures to be achieved.
3. The temperature throughout the tumor should be well-defined and uniform. The development of relative cool spots in a non-homogenous tumor may result in failure of cell kill and selection of cells with thermal tolerance (resistance to hyperthermia) within that area. Small differences in temperature may produce large differences in cell kill.
The above criteria lead to the following requirements, which, if fulfilled, will allow the accurate measurements needed to develop dose response to therapy relationships which are necessary to provide uniform treatment for all patients and evaluation of clinical studies.
1. The technique should enable induction of hyperthermia to a well-defined volume. The fall-off of temperature beyond the tumor volume should be steep.
2. The level of hyperthermia should be precisely controllable.
3. Temperature distribution within the tumor volume should be uniform at therapeutic levels.
4. It should be possible to control the heat transferred in different regions of the tumor volume.
5. The therapist and not the changing characteristics of the heated tumor should control the temperature within the tumor volume, to avoid overheating a necrotic liquefied tumor center or underheating a well vascularized growing tumor edge.
6. In addition, one should be able to accurately monitor temperature.
Applying these criteria to existing hyperthermia devices, reveals that while some devices have advantages in some areas, all have limitations. Non-invasive hyperthermia applicators, such as ultrasound and electromagnetic radiation, are easier to use than invasive techniques, but are limited in depth of penetration. Ultrasound has poor penetration in bone and air. External microwave beam heating is limited by a shallow depth of penetration and the development of standing waves, creating hot and cold spots.
Consequently, more recently, investigations have been conducted into the feasibility of using invasive applicators in the form of small diameter microwave antennas or probes as a means of producing local hyperthermia in cancerous tissue. In this form of therapy, antenna probes are inserted into the body through the esophagus or rectum, or directly into a tumor using a hollow plastic catheter.
Typically, these probes comprise a quarter-wavelength monopole antenna with frequencies in the 500 MHz to 3 GHz range. These antennae are referred to by workers in the hyperthermia field as a dipole, or a sleeve dipole. A folded back quarter wave choke forms one-half of the antenna length (S. Silver, "Microwave Antenna Theory and Design", Dover Publication, Chapter 8, p 241 and Electromagnetics, Vol. 1, No. 1, January-March 1981, p 58). The latter more nearly approximates a dipole antenna pattern.
These prior art dipole antennae suffer from a number of shortcomings, such as, poor impedance matching; high sensitivity to changes in the length of penetration of the probe into the body; poor uniformity in electric field and heating patterns produced; and lack of beam steering and heat sensing capabilities. J. W. Strohbehn, et al., "An Invasive Microwave Antenna for Locally-Induced Hyperthermia for Cancer Therapy", Journal of Microwave Power, 14 (4), 1979, pp 339-350; D. C. deSieyes, et al., "Optimization of an Invasive Microwave Antenna for Local Hyperthermia Treatment of Cancer", Thayer School of Engineering, Dartmouth College, July 7, 1980; J. W. Strohbehn, et al., "Evaluation of an Invasive Microwave Antenna System for Heating Deep-Seated Tumors", presented at the Third International Symposium: Cancer Therapy by Hyperthermia, Drugs and Radiation, Fort Collins, Colo., June 22-26, 1980.